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However, the molecular mechanism by which mitochondrial protein acetylation influences hepatic IR remains incompletely elucidated. To investigate this biology, GCN5L1 liver knockout mice (LKO), which exhibit blunted mitochondrial protein acetylation are utilized. Interestingly, the hepatocytes of LKO mice exhibit impaired insulin signaling and exaggerated endoplasmic reticulum (ER) stress. To explore putative mechanisms, protein\u2010interaction and acetyl\u2010proteome analyses are conducted following hepatic induction of GCN5L1. The mitochondrial chaperone GRP75 interacts with GCN5L1 and is acetylated on lysine residues K567 and K612 by GCN5L1 overexpression. Furthermore, GRP75\u2010K567\/612 acetylation reduces the assemble of IP3R1\u2010GRP75\u2010VDAC complex, which in turn leads to the maintenance of ER calcium homeostasis and insulin sensitivity. Interestingly, during high\u2010fat diet feeding, mitochondria\u2010localized GCN5L1 is significantly translocated to the cytosol. This translocation attenuates the acetylation of GRP75 at K567\/612 and consequently enhances ER\u2010mitochondrial calcium flux and induces ER stress. In parallel, deacetylation\u2010mimicking mutated GRP75\u2010K567\/612 promotes IR in vivo. Consequently, these findings demonstrate that the acetylation\u2010dependent modification of GRP75 plays a functional role in regulating overnutrition\u2010induced IR.<\/jats:p>","DOI":"10.1002\/advs.202508991","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:59:19Z","timestamp":1758880759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Acetylation of the Mitochondrial Chaperone GRP75 Governs ER\u2010Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance"],"prefix":"10.1002","volume":"12","author":[{"given":"Danni","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology State Key Laboratory of Experimental Hematology Tianjin Key Laboratory of Inflammatory Biology The province and ministry co\u2010sponsored collaborative innovation center for medical epigenetics NHC Key Laboratory of Hormones and Development Chu Hsien\u2010I Memorial Hospital, and Tianjin Institute of Endocrinology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Tianjin Key Laboratory of Cell Homeostasis and Major Diseases School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology State Key Laboratory of Experimental Hematology Tianjin Key Laboratory of Inflammatory Biology The province and ministry co\u2010sponsored collaborative innovation center for medical epigenetics NHC Key Laboratory of Hormones and Development Chu Hsien\u2010I Memorial Hospital, and Tianjin Institute of Endocrinology School of Basic Medical Sciences Tianjin Medical 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Hsien\u2010I Memorial Hospital, and Tianjin Institute of Endocrinology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology State Key Laboratory of Experimental Hematology Tianjin Key Laboratory of Inflammatory Biology The province and ministry co\u2010sponsored collaborative innovation center for medical epigenetics NHC Key Laboratory of Hormones and Development Chu Hsien\u2010I Memorial Hospital, and Tianjin Institute of Endocrinology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanni","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology State Key Laboratory of Experimental Hematology Tianjin Key Laboratory of Inflammatory Biology The province and ministry co\u2010sponsored collaborative innovation center for medical epigenetics NHC Key Laboratory of Hormones and Development Chu Hsien\u2010I Memorial Hospital, and Tianjin Institute of Endocrinology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Sack","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism 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